Inhibitors of HIV protease

Abstract

Compounds of formula (I): <IMAGE> (I) wherein: R1 is hydrogen, alkyl, aralkyl, -CORa, -CORb, -CSRa, -CSRb, -SO2Rb, -CONHRb, -CSNHRb, -CONRbRb or -CSNRbRb; R2 is hydrogen or alkyl; R3 is hydrogen, alkylidene, substituted alkyl, or Rb; R4 is optionally substituted alkyl, cycloalkyl, or aryl; R5 is RbO-, RbRbN-, RbHN-, aralkyloxycarbonyloxy or aralkyloxycarbonylamino, or R5 is -(CH2)p-D-(CH2)r-, where D is a single bond, carbonyl, oxygen, sulfur, -NH-, -(CH2=CH2)- or -NHCO-; and +E,uns p+EE and +E,uns r+EE are each 0 or an integer from 1 to 5; A is -(CH2)m-B-(CH2)n- where B is a single bond, carbonyl, oxygen, sulfur, -NH-, -(CH2=CH2)- or -NHCO-; and +E,uns m+EE and +E,uns n+EE are each 0 or an integer from 1 to 5; Ra is alkoxy, aralkyloxy, aryloxy or alkoxycarbonyl; Rb is optionally substituted alkyl, cycloalkyl, heterocyclic, aryl or arylalkenyl; and pharmaceutically acceptable salts and esters thereof and pro-drugs therefor, have the ability to inhibit the activity of HIV protease and may thus be used for the treatment and prophylaxis of AIDS.

We claim: 
     
       1. A compound of the formula ##STR6## wherein X is a chlorine atom, and R 1  is selected from the group consisting of ##STR7## pharmaceutically acceptable salts and esters thereof.   
     
     
       2. The compound of claim 1, selected from the group consisting of 1-[3-(N 2  -benzyloxycarbonyl-L-asparaginyl)-amino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-4-chloro-L-prolinamide and pharmaceutically acceptable salts and esters thereof. 
     
     
       3. The compound of claim 1, selected from the group consisting of 1-{3-[ N 2  -(2-quinoxalinecarbonyl)- L-asparaginyl]amino-2-hydroxy-4-phenylbutyryl}- N-t-butyl-4-chloro- L-prolinamide and pharmaceutically acceptable salts and esters thereof. 
     
     
       4. The compound of claim 1, selected from the group consisting of 1-{3-( N 2  -(7-methoxy-2-benzofurancarbonyl)- L-asparaginyl]amino-2-hydroxy-4-phenylbutyryl}-4-chloro- N-t-butyl- L-prolinamide and pharmaceutically acceptable salts and esters thereof. 
     
     
       5. The compound of claim 1, selected from the group consisting of 1-{3-[ N 2  -(1-methylindazol-3-yl-carbonyl)- L-asparaginyl]amino-2-hydroxy-4-phenylbutyryl}-4-chloro- N-t-butyl- L-prolinamide and pharmaceutically acceptable salts and esters thereof. 
     
     
       6. A compound selected from the group consisting of: 1-{3-[ N 2  -(2-quinoxalinecarbonyl)- L-asparaginyl]amino-2-hydroxy-4-phenylbutyryl}- N-t-butyl-4-chloro- L-prolinamide;   1-{3-[ N 2  -(4-aminophenoxyacetyl)- L-asparaginyl]amino-2-hydroxy-4-phenylbutyryl]-4-chloro- N-t-butyl- L-prolinamide;   1-[{3-[ N 2  -(4-benzyloxycarbonylaminophenoxy)acetyl- L-asparaginyl]amino-2-hydroxy-4-phenylbutyryl}-4-chloro- N-t-butyl- L-prolinamide;   1-{3-( N 2  -(7-methoxy-2-benzofurancarbonyl)- L-asparaginyl]amino-2-hydroxy-4-phenylbutyryl}-4-chloro- N-t-butyl- L-prolinamide;   1-{3-[ N 2  -(1-methylindazol-3-ylcarbonyl)- L-asparaginyl]amino-2-hydroxy-4-phenylbutyryl}-4-chloro- N-t-butyl- L-prolinamide; and pharmaceutically acceptable salts and esters thereof.